As is now more widely recognized, Panic Disorder often results in considerable emotional suffering and a reduction in quality of life. Although progress has been made in identifying its biological substrates, much about its pathophysiology and etiology remains obscure. Latest research findings in our laboratory and laboratories of other research groups point towards a central role for respiratory mechanisms. Experiments are proposed to investigate markers and mechanisms of Panic Disorder in and outside the laboratory. Respiratory, sympathetic, and parasympathetic measures in Panic Disorder patients of two types, those with and without prominent respiratory symptoms, will be examined and compared to measures in two groups without panic attacks, Generalized Anxiety Disorder patients and controls. In the laboratory the relative importance of several possible respiratory mechanisms will be determined by examining probe-specific and group-specific effects of several kinds of probes: increased inspired CO2, increased inspiratory resistance load, and decreased inspired O2. Each is known to produce feelings of suffocation at moderate intensities, and sometimes panic in Panic Disorder patients at high intensities. Respiratory responses to a noise stressor not directly linked to suffocation fears will serve as a comparison. To resolve contradictions in the literature about slower recovery from voluntary hyperventilation in Panic Disorder, which was a specific marker for Panic Disorder in one of our recent experiments, the effects of different durations of hyperventilation will be examined. In another experiment, central and peripheral chemoreceptor thresholds and sensitivities will be distinguished in Panic Disorder for the first time. Outside the laboratory two ways of recording pCO2 (transcutaneous vs. nasal prongs) will be compared methodologically, and it will be determined whether valid indices of respiratory sinus arrhythmia that take into account variations in breathing will distinguish patients with panic attack-related driving phobia from controls. The significance of this proposal lies in the possibility of its establishing specific and sensitive physiological markers of Panic Disorder, which could lead to better diagnosis and more appropriate treatment, facilitate research in the molecular genetics of Panic Disorder, and lead to a better understanding of dysfunctional biological control mechanisms.